Chapter 2Neurocognitive Deficits, Negative Symptoms,and Insight in Schizophrenia

Adrian Preda, Robert Bota, and Philip Harvey

Abstract The symptom domains of primary negative symptoms, insight and cog-nitive deficits in schizophrenia appear to overlap on a number of aspects. Thesedomains are: (1) relatively independent of the psychotic, affective and secondarynegative symptoms domains; (2) relatively persistent; (3) show only marginalimprovement with the available antipsychotic treatments; (4) are strongly correlatedin cross sectional measures, and (5) associated with outcome measures. Despite suchsimilarities the relationship between insight, negative and cognitive symptoms is yetto be clarified. Are we looking at independent categories of symptoms, at a primaryversus secondary symptoms type of correlation – e.g. insight deficits secondary tocognitive deficits – or maybe at a common neuropathological “lesion” or endophe-notype with multiple manifestations? Is the functional deficit an effect, a cause orjust another category that correlates with insight, negative and cognitive symptoms?In this chapter we will selectively review cross-sectional and longitudinal data toclarify the relationship between these schizophrenia domains. We conclude thatthe evidence to date suggests that we are in fact looking at independent symp-toms domains. This conclusion has important applications. At a theoretical levelthe implication is that, similarly to its clinical presentation, the underlying neuro-circuitry and pathophysiology of schizophrenia is diffuse and heterogeneous ratherthan localized and homogeneous. At a more pragmatic level the relative indepen-dence of the cognitive and negative symptoms suggests that effective interventionsmight need to selectively target each of the domains.

Keywords Cognitive deficits · Negative symptoms · Deficit · Insight ·Schizophrenia

A. Preda (B)Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USAe-mail: apreda@uci.edu

33M.S. Ritsner (ed.), Handbook of Schizophrenia Spectrum Disorders, Volume II,DOI 10.1007/978-94-007-0831-0_2, C© Springer Science+Business Media B.V. 2011

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Abbreviations

AMPA α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionateBDNF Brain-derived neurotrophic factorBP-I Bipolar disorder type ICOGS The consortium on genetics of schizophreniaCOMT Catechol-O-methyl transferaseCPT Continuous performance testsDTI Diffusion tensor imagingDSM Diagnostic and statistic manualFA Fractional anisotropyFE First episodeFGA First generation antipsychoticGABA γ-amino-butyric acidGAF Global assessment of functionICD International classification of diseaseIP Identical pairsMRI Magnetic resonance imagingNMDA N-methyl D-aspartatePANSS Positive and negative syndrome scalePD Personality disorderPSP Personal and social performanceQOL Quality of liferTMS repetitive transcranial magnetic stimulationSATCI The schedule for assessing the three components of insightSCID Structured clinical interview for DSM disordersSGA Second generation antipsychoticSTG Superior temporal gyriVBM Voxel-based morphometryWCST Wisconsin card sorting test

Definitions and Conceptual History

Dementia praecox, the name that Kraepelin [1] used to first describe schizophre-nia, is translated as early dementia. The name clearly implies the presence earlier inlife of cognitive deficits similar to those typically observed in much older patientsdiagnosed with dementia. In addition to different types of delusions and hallucina-tions, Kraeplin’s dementia praecox definition included cognitive impairment (e.g.attention, memory, orientation, language, and thought deficits) as well as nega-tive symptoms. Specifically, avolition/amotivation was seen as a core feature ofthe syndrome. In fact, Kraeplin’s description of the “amotivational syndrome” as a“weakening of those emotional activities which permanently form the mainspringsof volition”, followed by “emotional dullness, failure of mental activities, loss of

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mastery over volition, of endeavor, and of ability for independent action”, remains tothis day one of the best descriptions of negative symptoms. Kraepelin also describedhis patients’ lack of insight; referring to the patients’ inability to recognize they aresuffering from a mental illness and are in need of care; however he did not see thisas a characteristic trait of schizophrenia. Of note, Kraeplin’s original descriptionsimply stated what the clinical symptoms of dementia praecox were, without animplication of what might be primary versus secondary.

Following Kraeplin, Bleuler [2] differentiated between schizophrenia coreor fundamental symptoms, the “Grundsymptome”, and the “AkzessorischeSymptome” (accessory symptoms) of schizophrenia. In his “Grundsymptome”Bleuler included a number of negative symptoms, specifically abnormalities in asso-ciation, affect, ambivalence, relationship to reality (autism), and volition. What wenow label as catatonic features and positive symptoms, including delusions and hal-lucinations, in addition to disorders of attention, orientation, memory, consciousnessand motility, Bleuler saw as the “Akzessorische Symptome” (accessory or secondarysymptoms).

In the development of psychiatry as a science the Kraepelinian/Bleulerian fond-ness for description was followed by the Freudian determination to explain it all.Not surprisingly within a subjective hierarchy informed mostly by symbolism andmetaphor the unanalyzable cognitive deficits and unalluring negative symptoms fellout of favor. In this context, the re-classification of cognitive and negative symptomsas “secondary” might have been an unintended consequence of increased emphasison the much more colorful and fun to interpret Schneiderian first rank symptoms [3]including symptoms such as paranoia and abnormal perceptions. Noteworthy is alsothe fact that the 1950s witnessed chlorpromazine’s victory over the positive symp-toms of schizophrenia (i.e. delusions and hallucinations). This important event, inaddition to marking the birth of modern psychopharmacology, further reified thepositive symptoms as a biological cornerstone of psychosis. It is this combinationof historical circumstances that set the research cards against studying cognitiveimpairment and negative symptoms in schizophrenia.

Only following the advent of diagnostic systems heavily invested in reliabilitysuch as the PSE, the RDC and DSM III has the field been able to overcome itsprejudices and deem cognition and negative symptoms in schizophrenia as subjectsworthy of interest in their own right [4–6].

To illustrate, the Schneiderian belief that the first rank symptoms were pathog-nomic to schizophrenia and have prognostic value, while not supported by empiricalevidence and at odds with both Kraepelin’s and Bleuler’s views, has carried onthrough all the DSM and ICD editions. The present ICD 10 and DSM IV formu-lations of schizophrenia require the presence of only one first rank symptom for adiagnosis of schizophrenia [7, 8]. At the same time DSM IV lists lack of insightunder “Associate Features of Schizophrenia” while curiously acknowledging thataltered insight is “one of the most common symptoms” and “may be one of the bestpredictors of poor outcome” in schizophrenia. DSM IV also emphasizes that nega-tive symptoms and cognitive dysfunction are indicative of a poor prognosis (under“Course”), that cognitive dysfunction is “often present” and introduces a negative

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(deficit) dimension under “Alternate Dimensional Descriptors of Schizophrenia”.Yet, despite all the above, negative symptoms alone are not deemed sufficient forfulfilling the Criterion A DSM requirement for a diagnosis of schizophrenia andcognitive deficits are discussed only briefly under “Associated Features” [8].

Cognitive Deficits: What we have learnt is that the story of cognition inschizophrenia might be the very opposite of what we imagined it to be. Whilepositive psychotic symptoms may fluctuate during the course of the illness, thefact that cognitive deficits are relatively constant raised important question aboutwhat constitutes core or primary, versus secondary deficits [9]. We used to think ofschizophrenia as a building where the ungluing of meta-cognition and other higherprocesses cracks its cognitive “bricks” and eventually results in the collapse of thewhole edifice. Based on multiple lines of evidence we now think just the oppo-site: already cracked cognitive bricks, further damaged by wear and tear, eventuallycrack for good and eventually result in the ruin of the whole edifice. Patients withschizophrenia consistently perform 1–1.5 to 1.5–2 standard deviations lower thannormal controls on a variety of neuropsychological tasks targeting attention, work-ing memory, processing speed, problem solving and social cognition, among others[10, 11]. In their meta-analysis of 43 separate samples of 2,204 first episode (FE)patients Mesholam-Gately and colleagues [12] conclude that cognitive deficits in FEschizophrenia are similar to those reported in chronic schizophrenia. Furthermore,the study reports an increase in FE deficits compared to earlier premorbid IQ levelsand stability of course afterwards. While the significant heterogeneity of effect sizesacross studies limits the validity of the conclusions, such data suggests that cognitivedeficits appear before other clinical symptoms and tend to remain stable overtime.Rather than an effect, cognitive deficits might be a cause (or even the cause – but theevidence supporting this hypothesis is less convincing at this time) of schizophrenia.In other words, dysfunction at the level of basic cognitive processes such as atten-tion, processing speed, working memory, among others, might just be the reason forthe ungluing and collapse of the higher functions.

Negative Syndrome: The negative symptoms are defined as reduction or evenabsence of a normal psychological function. A number of negative symptoms havebeen described over time but the current use typically refers to poverty of speech(alogia), avolition-apathy, amotivation, physical anergia and anhedonia-asociality[13, 14]. The history of the concept can be traced back to a paper published in1861 by Sir John Russell Reynolds (1828–1896) who described positive and nega-tive symptoms as an “excess or negation of vital properties” (for a review, see Perce2004 [15]). “Superimposed” behaviors such as abnormal movements but also para-noid delusions and hallucinations were labeled as positive symptoms; “losses” ofsensation, feeling, motor abilities (culminating with coma) were labeled as nega-tive symptoms. Around the same time Herbert Spencer’s evolutionary theory, andspecifically his ideas about the evolution and dissolution of the nervous system,were gaining preeminence. Hughlings Jackson integrated Spencer’s theories andReynolds’ observations and concluded that positive symptoms represented an exces-sive expression of normally inhibited neural processes, while negative symptomswere due to a more diffuse Spencerian dissolution of neural function:

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Anatomically, the negative elements are losses of adjustment of the organism, as a whole,to the environment in the order, according to the “depth” of the dissolution, from the mostspecial and complex of them towards the most general and simple. [16]

Interestingly, Jackson’s positive/negative classification, while speculative, impliedthat negative symptoms would have a poorer course, response to treatment andprognosis, which has now been confirmed by empirical evidence.

The demise of psychoanalysis marked a change in the philosophy underly-ing the diagnostic research process in psychiatry: from a pre-DSM III etiological,analytically informed approach to a post-DSM III, atheoretical, descriptive nosol-ogy. Strauss et al. [17] work discussing of 3 different schizophrenia domains (i.e.positive symptoms, negative symptoms and a disorder of relation) can be under-stood in the context. Even if it revamped interest in negative symptoms Strausset al. [17] contribution did not generate enough momentum (or data) to result ina separate negative symptom core for the DSM III [6] diagnosis of schizophre-nia. However, “the one disorder, multiple core domains” theory of schizophrenia,resulted in a number of theoretical models, parsing a presumably unitary concept(i.e. schizophrenia) in different subtypes: type I and II, positive and negative symp-toms type, and deficit and non-deficit schizophrenia [13, 14, 18–20]. All thesemodels share the assumption that negative symptoms are a core deficit and should beseparated in a distinct subtype due to its different course, prognosis and response totreatment.

The negative symptoms of schizophrenia are further classified as primary (per-sistent, intrinsic to schizophrenia) and secondary (temporary, associated with andpresumably due to other factors such as depression, medication adverse effects, orpositive symptoms [21]. While secondary negative symptoms may be reduced bytreating the causative agent, primary negative symptoms are viewed as enduringand persisting between psychotic episodes [22–25].

Insight: The origin of insight can be traced back to the psychoanalytic litera-ture. However, while psychoanalysis conceptualizes insight as a state of sudden“illumination” of a previously unconscious process, insight in schizophrenia is amultidimensional concept referring to awareness of illness, its specific symptomsand their consequences, as well as need for treatment [26, 27]. Insight is enduringrather than temporary and it refers to the patient’s ability to understand that someof his non-reality based experiences (usually hallucinatory experiences and delu-sional representations) are secondary to having schizophrenia rather than “real”.Awareness and attribution of both current and past symptoms represent specificaspects of insight. Additional dimensions of insight include a more global under-standing of the diagnosis and need from treatment [28]. Insight has been variouslydiscussed as an independent symptom domain, as secondary symptom (correlatedwith affective symptoms), or as a dependent symptom that is part of a broaderdomain including: (1) positive symptoms (where insight is a type of delusion);(2) negative symptoms (where insight, as other negative symptoms, is a decreaseof a normal function, i.e. awareness); and (3) neurocognitive dysfunction (whereinsight deficits are thought to be similar to the better understood syndrome of

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anosognosia described in some neurological syndromes). Our rationale for includ-ing it in this chapter is based on proposed theories about its shared characteristicswith the negative and cognitive symptoms domains: correlates with premorbidfunctioning, negative prognostic value when present at the onset of illness and base-line, course, and association with functional outcomes, and more specifically socialdysfunction.

Epidemiology

Demographic Variables

Cognitive Impairment: Cognitive functioning is associated with a number of demo-graphic variables, including educational attainment, ethnicity, and sex [29]. Thesedemographic variables are also associated with cognitive performance in peoplewith schizophrenia as well [30]. The influence of education and ethnicity is roughlythe same level of association with cognitive variables in people with schizophreniaas in healthy individuals. However, since people with schizophrenia are commonlyfound to have lowered levels of educational attainment compared to others fromsimilar socioeconomic backgrounds, the influence of education on cognition maybe somewhat more salient. Further, people with schizophrenia routinely manifestreduced levels of educational attainment than their parents and siblings [31]. Asdescribed below, reduced cognitive performance is present prior to the occurrenceof any other symptoms of schizophrenia, possibly being a contributory factor toreduced educational attainment and suggesting a direction of relationship whereinearly cognitive impairments increase the challenge associated with school

Negative Syndrome: Primary negative symptoms have been associated with poorpremorbid function, male gender and low Intelligence Quotient [14]. Male gendernot only increases the risk for negative symptoms but male schizophrenia patientshave also been reported to have more severe negative symptoms [32, 33]. Men alsopresent more frequently with flat affect than women patients with schizophrenia[34–38].

Insight: Lack of insight appears to be a culturally independent symptom ofschizophrenia. Amador et al. [28] reported that acute schizophrenia was associatedwith poor insight in all the countries and cultures surveyed in the World HealthOrganization International Pilot Study of Schizophrenia. The evidence about demo-graphics association with overall insight or insight specific domains is mixed. Thepreferred demographic distribution for negative and cognitive symptoms does notseem to apply for insight deficits n schizophrenia. In their study of 42 patientswith schizophrenia and 22 patients with bipolar disorder with psychotic featuresArduini et al. [39] reported no difference between male and female in insight scores.Schwartz et al. [40] studied 66 patients with chronic schizophrenia and found noassociation between insight and demographic variables. However, in a recent largescale multi-site clinical trial of 303 subjects with schizophrenia baseline insightcorrelated positively with premorbid functioning and level of education [41].

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Breadth of Impairments: Genetics, Family Historiesand First Degree Relatives

Cognitive Impairment: Cognitive impairments have been recognized in the relativesof people with schizophrenia for decades [42]. Studies of cognitive impairmentson the part of relatives have had some of the same results as studies of schizoty-pal personality disorder (PD). Profiles of impairment appear similar and the levelof impairment is somewhat reduced compared to schizophrenia. These impairmentshave long been characterized as “markers of vulnerability” in that these impair-ments may well identify individuals at extra high risk as noted above. However,until recently a definitive single-sample study was lacking and that study is nowpartially completed.

Concurrent with the development of the MATRICS initiative, the Consortiumon Genetics of Schizophrenia (COGS) study sought to identify genetically-linkedvariation in cognitive performance [43]. This research study followed up years ofless systematic research on genetic influences on cognition in schizophrenia and thegeneral population. The previous work had implicated multiple different potentialsusceptibility genes for cognitive changes, including COMT, BDNF, and multipleother candidates. These studies have consistently shown that multiple aspects ofcognitive functioning are related to gene expression variants [44].

It has been known for years that cognitive impairments tend to have a geneticcomponent, and that estimates of the heritability of neuropsychological perfor-mance is quite high, with average heritability quotients over 0.40 [34]. Many ofthe more functionally relevant aspects of cognitive impairment are known to beconsistently heritable, including episodic memory (heritability range = 0.3–0.6),attention/vigilance (mean = 0.54), working memory (range = 0.3–0.6), and execu-tive functioning (range = 0.3–0.6). Thus, cognition is a heritable trait in families ofpatients with schizophrenia, and determining the relative importance of the herita-ble components of cognition for functional disability in schizophrenia is important.As these measures were selected for use in multi-site trials, they are ideal for use inlarge scale treatment studies.

Negative Syndrome: In the Roscommon Family Study negative symptoms in allprobands diagnosed with nonaffective psychoses predicted corresponding dimen-sions of schizotypy in the patients’ nonaffected first degree relatives as well as oddspeech, suspicious behavior, and social dysfunction [45]. While the associated socialdysfunction was expected, the authors commented that the association with oddspeech and suspicious behavior was surprising. As a possible explanation they notedthe overlap between suspiciousness (a positive factor) and the negative factors aso-ciability and poor rapport. These findings remained significant when probands witha nonschiophrenics psychosis were included, which suggest a negative symptomsdimension on the spectrum of schizophrenia disorders, starting with schizotypalpersonality traits and ending with schizophrenia psychosis. Furthermore, positivesymptoms in patients predicted positive schizotypal traits and negative symptomspredicted negative schizotypal traits in relatives. These findings suggest that in addi-tion to a continuum of risk for both positive and negative symptoms these are twoetiologically distinct domains of schizophrenia [45].

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A family history of schizophrenia has been reported to correlate with a moresevere course of schizophrenia, including an increased risk for negative symp-toms. The presence of pervasive negative symptoms is considered a marker ofrelatively high genetic loading for schizophrenia [46]. In their recently publishedmeta-analysis of 12 negative symptoms studies Esterberg et al. [47] reported that afamily history has a small but significant effect on negative symptoms. Cardno et al.[46] found that the risk of schizophrenia in relatives was predicted by the presence ofpervasive negative symptoms (OR: 9.44, 95% CI = 1.98–45.01) and the absence ofpervasive positive symptoms (OR = 0.09, 95% CI = 0.01–0.78) in probands, wherepervasive negative symptoms were defined by the presence of all of the symptoms:social withdrawal, autistic behavior, poverty of thought/speech, and flat affect.

Insight: Is family history relevant for insight deficits? As discussed above there isa familial transmission of cognitive deficits and negative symptoms; also both cog-nitive deficits and negative symptoms appear to co-aggregate with insight deficits[48]. Therefore it can be assumed that secondary (to cognitive impairment) insightdeficits can be seen in families with schizophrenia. However, this does not clarify ifthere is a familial transmission or familial risk diathesis for primary insight deficitsin schizophrenia. To address this question Danki et al. [49] studied the relationshipsbetween a family history of schizophrenia and insight deficits in a Turkish sample of66 stable patients with a SCID based diagnosis of schizophrenia. The Schedule forAssessing the Three Components of Insight (SATCI) overall score and the scores of5/8 SATCI subscales (i.e. awareness of illness, awareness of a mental illness, expla-nation of the illness, belief in the delusion, explanation of experiences, and reactionto not believing – optional eighth question), were all significantly lower in patientswith a family history of schizophrenia [49, 50]. While interesting, these findingsare based on a single site cross sectional study with a relatively small sample size;thus, they remain preliminary until future replication. At the same time, while Dankiet al. [49] results appear to indicate there is a family effect of schizophrenia oninsight, they do not answer the more direct question about the familial transmissionof insight deficits in schizophrenia.

Breadth of Impairments: Schizophrenia Spectrumand Other Disorders

Cognitive Impairment: There are other conditions that are related to schizophreniaand several of these conditions have similar cognitive impairments. Most simi-lar from a phenomenological perspective is schizotypal personality disorder. Thiscondition manifests variants of positive and negative symptoms of schizophre-nia, at slightly reduced levels of severity, and there is clear evidence of cognitiveimpairments as well. These impairments have similar signatures compared toschizophrenia, with slightly reduced levels of severity. For instance, in a series ofstudies of a large sample of people with schizotypal PD, we found that the profile of

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impairments was similar to that seen in schizophrenia, greater in severity than peo-ple with other personality disorders, and approximately one half as severe as thoseseen in schizophrenia [51, 52]. These findings are widely replicated and it is believedthat it is likely that cognitive impairments similar to those seen in schizophreniamay be a common feature, but that alterations in the subcortical dopaminergic func-tioning that are associated with schizophrenia are generally lacking in people withschizotypal personality disorder.

Bipolar Illnesses: The majority of studies in the medical literature tend to focuson schizophrenia and demonstrate somewhat greater impairment in schizophreniacompared with BP-I [53, 54]. Although neuropsychological functioning in BP-Ihas been less extensively studied than in schizophrenia, evidence does suggest thatmood disorder patients frequently manifest neuropsychological deficits in atten-tion, executive, and memory functions [53–60]. Symptomatic BP-I patients havebeen shown to have widespread cognitive abnormalities [61]. Evidence from studiessupports the hypothesis that there are persistent residual neuropsychological impair-ments in patients in euthymic phases of illness [59, 62, 63]. Neuropsychologicalstudies directly comparing patients with schizophrenia and BP showed relativelyequivalent dysfunction on the Wisconsin Card Sorting Test [64], visual backwardmasking [65, 66], and overall neuropsychological function [57, 67].

In a recent study of first episode patients who were clinically stabilized from afirst episode that included psychotic symptoms, we [68] found that the profile ofclinically stable patients with bipolar and unipolar affective disorders was essen-tially identical to that seen in schizophrenia patients. Similar to the results forrelatives of people with schizophrenia and individuals with schizotypal PD, theseverity of impairment in people with schizophrenia was about twice as great com-pared to normative standards as the patients with affective disorders who did notdiffer substantially.

Although many BP-I subjects can have periods of syndromal remission (anddo not typically have the same prevalence of disability or long-term deteriorationas those with schiophrenia), these periods of “recovery” are not accompanied bynormalization of social, familial, and occupational role function for a substantialproportion of cases [69]. A meta-analysis of 17 studies examining psychosocial out-come in patients with BP-I found that 30–60% of them fail to regain full functioningin social and occupational domains [70]. Mixed affective states [71], psychoticsymptoms [72, 73], and more previous episodes [74–77] are among the variablesthat have found to be associated with poor outcome. A recent report from a lon-gitudinal first episode study of bipolar disorder with manic episodes found thatexperiencing symptomatic relapse and remission was a relatively common occur-rence compared to functional recovery [78]. Although 43% of first episode bipolarpatients appeared to experience functional recovery (compared to only 18% offirst episode patients with schizophrenia), the criteria for functional recovery wasonly return to premorbid functioning, with no requirement for successful ongoingeveryday outcome (and this finding is still a very low rate of normal functionaloutcome).

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Negative Syndrome: In a multicenter retrospective study of 1,452 patients diag-nosed with schizophrenia spectrum disorders (schizophrenia, schizophreniform, andschizoaffective disorder) the majority of the patients (57.6%) had at least oneor more negative symptoms, while primary negative symptoms were reported in12.9% of patients [79]. The patients with schizophrenia had more frequent andmore severe negative symptoms than patients with a diagnosis of schizophreniformor schizoaffective disorder [79]. Persistent negative symptoms are more prevalentin schizophrenia than in depressed patients, where negative symptoms also seemto correlate with depressive symptoms [80]. In a long term prospective study ofschizophrenia, schizoaffective and affective disorder patients, the prevalence ofnegative symptom was found to be high at the 15 year follow up: 75% of theschizophrenia patients, 68% of the schizoaffective patients, and 44% of the patientswith affective disorders where found to have at least one negative symptom [81].However, schizophrenia patients had much more severe negative symptoms at the 15year follow up compared to both the schizoaffective and affective disorder controls[81, 82].

Insight: Converging evidence suggests that there is a type of insight deficits thatappears to be specific to schizophrenia. Insight deficits in schizophrenia appear tohave a different course that of insight deficits seen in affective disorders. There isless variation in the course of insight deficits course in schizophrenia (trait like) vs.a state dependent course in affective disorders. Also, schizophrenia patients havemore severe of insight deficits than patients with any other major psychiatric diag-nosis, including schizoaffective disorder. In a multisite, cross-sectional study of 412patients with schizophrenia, schizoaffective and mood disorders (with and withoutpsychotic features) poor insight was more prevalent and more severe in patientswith schizophrenia [83]. Wifffen et al. [41] also found lower insight in their cross-sectional measurement of insight in schizophrenia patients (N = 213) comparedwith schizoaffective patients (N = 90).

In people with schizophrenia there is a positive correlation between insight andsymptoms of depression, paranoia and anxiety [84, 85]. Insight preservation in thesedomains is important because it predicts quicker resolution of symptoms, with lesshospitalization in the period of time leading to relapse [86]. At the same time, in a 2year longitudinal study, patients with schizophrenia with other Axis I comorbiditieshad less improvement in their awareness of illness at 12, 18 and 24 months followup points and less insight into the consequence of illness at 18 and 24 months followup [87].

Neurobiological Considerations

When it comes to insight, the neurobiological literature is remarkable for its dearthof reports. The situation is quite the opposite for cognitive deficits and, to someextent, negative symptoms where, with the accessibility of sophisticated brain imag-ing and neurophysiology tools and following the mandate set out by the MATRICS

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guidelines, the pace of publishing of new reports has had a fairly steep slope.Reviewing the wealth of interesting reports is beyond the scope of this limitedreview. Thus for practical reasons we will review only a few selected studies andfocus on a summary of findings with special relevance to cognition and negativesymptoms.

Brain Structural Abnormalities

Ventricular and Whole Brain Volumes: Since the advent of the first neuroimag-ing technologies, there have been findings of reductions in cortical volume andincreased ventricular size in people with schizophrenia. There was a previous beliefthat volumetric reductions and increased ventricular size were associated with spe-cific profiles of symptoms specifically cognitive impairments and deficit syndrome[23], but the bulk of the evidence has suggested that small increases in ventricularsize, not great enough on average to be viewed as clinically abnormal, are presentin many people with schizophrenia. That said, there is some evidence of correla-tion between medial temporal lobe volume and memory impairment. These corticalchanges are present at the time of the first episode or even during prodromal peri-ods prior to formal diagnosis and have been reported quite consistently to progress,in terms of gray matter loss, over follow-up periods starting at that time. Evidencedoes suggest that these changes are slightly greater in individuals with poor life-time functional outcomes who, consistent with the evidence presented above, are atthe highest risk for experiencing cognitive and functional declines in later life [88].Further, some studies have shown that ventricular enlargement is correlated withglobal cognitive impairments. Findings of decreasing cortical volume or increasingventricular size in longitudinal studies have lead to the suggestion that these changesare reflective of active illness processes [89].

Gray Matter Changes: Advances in neuroimaging technology have led to theability to separately examine gray and white matter. Consistent findings suggestthat gray matter volumes are reduced in schizophrenia across the lifetime courseof the illness. Recent studies have suggested that these changes in cortical volumeare associated with an increased frequency of psychotic relapses, starting at thetime of the first episode. These findings are consistent with the late-life findingsreviewed above suggesting that more severe and unremitting psychotic symptomsare associated with cognitive decline over follow-up periods ranging from 3 to 6years in older patients. Thus, progressive loss of cortical gray matter, correlated withfrequency of psychotic episodes, is a potential determinant of cognitive impairmentsand negative symptoms in schizophrenia.

A number of brain regions have been studied in relation to negative symptoms.Kim et al. [90] reported that superior temporal gyri abnormalities are present atbaseline and correlate with negative symptoms severity even in neuroleptic naïvepatients. A prospective 3-year volumetric MRI study found that volume changesin the left anterior amygdala-hippocampal complex significantly correlated withPANSS negative symptoms change over the study period [91]. A bilateral decrease

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in gray matter volume in the superior temporal gyri and anterior amygdala –hippocampal complex has also been shown in a small cross-sectional region ofinterest MRI study comparing male chronic schizophrenia patients with predom-inant negative symptoms vs. healthy controls [92]. Such longitudinal findings,while interesting, are limited by the confounding effect of concomitant medications(mainly first generation antipsychotics – FGAs in the cited studies). Interestingly,Meisenzahl et al. [93] failed to replicate these findings; however, their sampleappears unique in terms of clinical stability and a higher proportion of patients sta-bilized on second generation antipsychotics (SGAs) at the time of the study. Luiet al. [94] using an voxel-based morphometry (VBM) approach found negative cor-relations between temporo-precuneus connectivity and total PANSS scores as wellas scores for negative symptoms and anergia.

White Matter Abnormalities: Many theories of cognition and negative symptomsin schizophrenia have focused on impairments in connectivity as their central fea-ture. In addition, there are several neuropathological abnormalities that implicatewhite matter changes. Most central is the finding that neuronal density is increasedin certain brain regions in schizophrenia, in the absence of increases in cell num-ber [95]. This finding combines with findings of decreased cellular arborizationand fewer synaptic contacts (i.e. fewer dendritic spines) to suggest that findingsof global reductions in cortical volumes could be due to abnormalities in white mat-ter. These indirect suggestions have been confirmed by a series of neuroimagingstudies that suggest abnormalities in the organization and integrity or cortical whitematter. Central among these findings have been studies using diffusion tensor imag-ing (DTI) [96]. Through measuring water diffusion in myelin sheaths, it is possibleto visualize the orientation of these axons. Axons organized in parallel will havehigher anisotropy values and be organized more coherently. Multiple studies havereported reductions in fractional anisotropy (FA) in people with schizophrenia com-pared to healthy controls, suggesting reduced coherence of white matter tracts. In avery recent study, we reported that the age of the patient (ranging in age of 18–80),was associated with tract specific reductions in fractional anisotropy in the corpuscallosum in comparison with healthy controls who were similar in age [97]. Thus,these findings do provide an initial suggestion of progressive deterioration of whitematter in people with schizophrenia.

Pyramidal Cells: Approximately 75% of cortical neurons are pyramidal cells, sodesignated because of their triangular shape. These neurons utilize glutamate as atransmitter and are regulated by interneurons, which utilize the inhibitory transmit-ter γ-amino-butyric acid (GABA). The suggestion has been made that the reasonfor increased density in the absence of loss of neurons is due to reduced number ofaxons and dendritic spines attached the pyramidal cells. An implication of this isloss of afferent inputs from the thalamus, which would lead to reduced cortical acti-vation [98]. A possible mechanism of this particular structural abnormality could bean excessive degree of normal pruning processes which reduces the total number ofdendrites during adolescence. A further, and more speculative possibility, is that oftriggered apoptosis, possibly induced by altered dopamine and glutamatergic func-tioning. In either case, increased neuronal density is one of the more consistently

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detected neuropathological findings in schizophrenia post-mortem tissue and onethat suggests a direct connection between abnormal cortical structure and functionalactivity of critical brain regions in schizophrenia.

Brain Neurotransmission Abnormalities

The section above gives a sense of the relationships between neuronal factorsand patterns of distribution of cortical activation in people with schizophrenia.Schizophrenia has been extensively studied as a disease of impaired neural trans-mission due to the discovery of the antipsychotic effects of chlorpromazine in the1950s. Recent increases in the understanding of the interactions between differentCNS neurotransmitters have lead to a more sophisticated understanding of the pro-cesses of cellular activation and communication in the pathophysiology of cognitiveimpairments in schizophrenia.

Dopamine: The primary effect of antipsychotic medications is to block dopamineD2 receptors in the corpus striatum. All effective antipsychotic medications havethis properties and all medications that have been tried as antipsychotic medica-tions that lack this effect have failed in clinical trials. Several influential theories ofcognitive impairment in schizophrenia have focused on cortical/striatal dopaminebalance. In healthy individuals, increased activation of cortical dopamine neuronsis associated with reductions in striatal activity and vice versa, reflecting a regula-tory relationship between these regions. In contrast, there is apparently a disjunctionin these regulatory processes in people with schizophrenia and blockade of striataldopamine receptors does not lead to a corresponding increase in cortical dopaminetone.

Reduced cortical dopamine activity has been a prominent idea regarding the ori-gin of cognitive impairments and negative symptoms of the illness [99]. Many cog-nitive functions are related to dopaminergic activity and compounds that increasedopamine transmission, such as amphetamine, lead to improvements in these func-tions. For example, attention, working memory, and related executive functions aswell as some negative symptoms are improved with amphetamine treatment andreduced regional cortical activation, detected with fMRI techniques as describedabove, is associated with impaired performance on these types of tasks or increasedseverity of negative symptoms. Direct stimulation of cortical dopamine receptorswith dopamine D1 agonists can reverse the adverse of effects of aging and chronicantipsychotic treatment on working memory performance in monkeys, again sug-gesting the dopamine-relevance of many of the common cognitive impairments inpeople with schizophrenia.

Other evidence implicating dopamine in the cognitive impairments seen inschizophrenia comes from studies of the genetic variants associated catehol-O-methyl-transferese (COMT) [100]. There are two polymorphisms associatedwith this gene, valine/VAL and methionine/MET, with the VAL allele asso-ciated with greater catabolic potential in the DA receptor region and hence

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reduced levels of available dopamine. VAL–VAL homozygotes have been shownto have reduced levels of cognitive functions that are relevant to schizophre-nia, including working memory and executive functioning, Although the evi-dence for COMT as a susceptibility gene for schizophrenia is limited, the factthat this dopamine-relevant genetic variation is broadly associated with cogni-tive functioning, including in individuals with schizophrenia spectrum personalitydisorders, again indicates the role of dopamine in the cognitive abnormalities inschizophrenia.

Glutamate: Glutamate is an excitatory transmitter that is widely distributedin the CNS, but one of the potentially important locations for these receptorsis on dendritic spines. There are at least two receptor subunits for glutamate:N-methyl D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), both of which are also widely distributed. NMDA antag-onists such as ketamine and phencylclidine (PCP) trigger syndromes in healthyindividuals that are a close analogue to schizophrenia, including positive andnegative symptoms, impairments in communication, and cognitive deficits [101].People with schizophrenia are even more sensitive to these effects than healthyindividuals.

There are two domains where glutamatergic abnormalities might cause brainchanges and cognitive impairments. One is the suggestion that glutatmergic hypoac-tivity, as would be induced by chronic hyperdominergic activity, similar to theeffects of PCP and ketamine, can trigger apoptosis. These programmed cell deathprocesses would be difficult to detect at post-mortem because they do not neces-sarily cause gliosis at the time of occurrence. At the same time, this is a difficultidea to test because post-mortem tissue would have to be obtained during a periodof active apoptosis and these occurrences may be sporadic in nature. A second areawhere glutamatergic abnormalities could be related to cortical changes is throughtheir potential direct effect on white matter. Chronic glutamatergic hyperactivity,which could be a consequence of impaired DA-glutamate interactions, has beenproven to be toxic to oligodendrocytes. This process may be due to induction ofdysregulation in calcium homeostasis and increased intracellular calcium. As oligo-dendrocytes are damaged, demylination can occur, which further reduces the abilityof neurons to modulate glutamate activity. Thus, alterations in cortical white mat-ter previously detected in DTI studies could possibly arise from glutamatergicprocesses, suggesting a mechanism through which psychosis, cognitive impair-ment, negative symptoms and disorganized behavior may be directly linked to eachother.

A final mechanism through which glutamatergic dysregulation could impact oncognitive functioning is through disruption of dopamine input to pre-frontal siteswhere critical cognitive operations are performed. Impaired excitatory input to cor-tical DA receptors could lead to chronic changes in their functioning, on bothfunctional and morphological levels. One potential consequence of this process,suggested by Lewis and Sweet [102], is that chronic reductions in excitatory inputto cortical D1 receptors could lead to compensatory, but ineffective, upregulation ofthese neurons. This upregulation could then cause a consequential down regulation

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in the synthesis of GABA. As GABA itself regulates the level of glutatmatergicfunctioning, such a process could contribute to further dysregulation in the balanceof these transmitters

GABA: Post-mortem data has found reduced levels of GABA signaling in a criti-cal interneuronal subsystem: chandelier cells [103]. About 33% of interneurons thatcontain GABA were found to express essentially undetectable levels of a criticalregulator of GABA synthesis: glutamic acid decarboxylase -67 (GAD-67). GAD-67 is an enzyme that regulates production of GABA and it is highly responsiveto excitatory input directed towards GABA-containing interneurons. Thus reducedexcitatory signaling into GABA neurons would lead to reductions in synthesisof GABA. Interestingly, levels of signaling of the primary transporter of GABA,GABA transporter 1 (GAT-1), are also undetectable in these same interneurons. AsGABA regulates levels of glutamatergic activity, decreased GABA functioning hasthe potential to contribute to the cascade of reduced cortical input, compensatoryupregulation of D1 receptors, and maintenance of multi-system dysregulation ofneuro transmitters. It has been suggested that GABAergic dysfunction is at the rootof synaptic plasticity deficits in schizophrenia (for a review, see Costa et al. [104]).Several lines of evidence support the hypothesis that GABAergic downregulation,associated with reduced reelin secretion from GABAergic neuron axon terminalson dendrites, somata and the axon initial segment of pyramidal neurons, might beresponsible for the decreased PFC neuropil of schizophrenia patients. While neu-ropil findings have been reported in post-mortem studies, a number of in vivo studiesreported that PFC changes in schizophrenia associated with both cognitive deficitsand negative symptoms,

Acetylcholine: Acetylcholine is another transmitter potentially associated withcognitive changes in schizophrenia. In specific the nicotinic receptor subsystems ofthe cholinergic system appear to be altered in people with schizophrenia. There areseveral lines of evidence in this regard. Expression of the nicotinic alpha-7 recep-tor in the prefrontal cortex is altered in both people with schizophrenia and theirrelatives. Individuals with schizophrenia are more likely to smoke than the gen-eral population, starting prior to the onset of their illness, as well as smoking moreheavily and extracting more nicotine from cigarettes than nonschizophrenic fellowsmokers [105]. There have been postmortem reports of altered nicotinic receptordensity in people with schizophrenia as well, but it is challenging to rule out theeffects of smoking in that regard.

There has been limited evidence of alterations in muscarinic receptor systemsin schizophrenia. Post-mortem studies have not found reductions in indices ofmuscarinic activation or in levels of acetylcholine. However, one study reportedreduced levels of cholinergic neurons in the ventral striatum in schizophrenia, in theabsence of any evidence of other neurodegenerative changes. One possible confoundthroughout this research is the use of antimuscarinic medications to treat extra-pyramidal side effects of antipsychotic medications. The long-term effects of thesemedications are unknown and whether their use in early and middle life could influ-ence the postmortem detection of illness-related alterations in muscarinic activity isuncertain.

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Functional Changes in Brain Activity

The original conceptualization of brain dysfunction during cognitive processingon the part of people with schizophrenia was “hypofrontality”. At the same time,negative symptoms of schizophrenia are thought of as reflecting a frontal lobedysfunction (for a review, see Semkovska et al. [106]). Studies of high-load execu-tive functioning, attentional, and working memory paradigms consistently revealedreduced relative activity in the regions roughly corresponding to the dorso-lateralprefrontal cortex when compared to the brain activation of healthy individuals per-forming similar tasks. Recently, it has been found that such tasks are not associatedwith a specific localized reduction in regional brain activation, leading to small totallevel of brain activity, but rather with similar overall levels of brain activation inhealthy and schizophrenia populations and a differential regional pattern of distribu-tion. In specific, it has been reported consistently that reductions in anterior frontallobe activity are associated with increases in activation in other regions, typically theanterior cingulated, more posterior frontal regions, and the occipital cortex, whencompared to healthy individuals.

Hypofrontality and/or a fronto-temporal disconnection have been proposed anunderlying neurocircuitry abnormalities resulting or contributing to the formationand maintenance of negative symptoms.

The hypothesis put forward to explain these apparently contradictory findingsis the idea the schizophrenia patients may have a different memory-load activationresponse curve in the dorsolateral prefrontal cortex than controls. A typical obser-vation is that dorsolateral activity increases as task load increases, until capacity isexceeded, at which point dorsolateral activity decreases on the part of people withschizophrenia [107]. Callicott et al. [107] suggested that the relationship betweentask load and dorsolateral activity may not be different in schizophrenia and healthyindividuals; the load-activity curve may be the same, but patients may have lowercapacity leading to a decline in activity at loads processing loads lower than incontrols. Glahn et al. [108] performed a meta-analysis of brain activation studiesin schizophrenia using the N-back task, finding clear support for hypoactivation inthe dorslateral prefrontal cortex in schizophrenia patients. At the same time, theyalso documented consistently increased activation in the anterior cingulate and leftfrontal pole relative to controls. This pattern of findings suggests that dorsolateraldisturbances in schizophrenia during executive tasks do not represent focal abnor-malities of a specific neuroanatomical region, but probably an impairment in theability to engage functional networks subserving executive functions [109]. Manyof the functional imaging studies that have investigated cortical brain activation dur-ing performance of episodic memory tasks in schizophrenia have also demonstratedabnormalities in a range of prefrontal regions, including both decreased activityand increased activity. Studies of prefrontal activation during episodic memoryencoding have been more likely to find decreased than increased activation. Thesestudies have shown reduced activation in ventrolateral prefrontal regions, includ-ing BA47 and BA45, regions associated with semantic elaboration or encodingof information in memory (for a review see Barch [110]). It has been suggested

2 Neurocognitive Deficits, Negative Symptoms, and Insight in Schizophrenia 49

that reduced activation in these regions reflects a failure to generate and/or applyeffective encoding strategies among individuals with schizophrenia.

The anatomic components of the hypothetical neural network underlying cog-nitive dysfunction and the primary negative symptoms and are not completelyunderstood but, on the basis of converging lines of evidence from nonhu-man primates and from neuroimaging studies of humans, the prefrontal cortex,specifically the dorsolateral prefrontal (DLPFC), parietal, temporal and anteriorcingulated are thought to play critical roles. Reminding of the Jacksonian dif-fuse neural dissolution theory type II schizophrenia patients have smaller brainswith bigger cerebral ventricles [18]. Several studies have suggested that pri-mary negative symptoms are functionally localized to the frontal and parietalcortices [111].

Rossell et al. [112] evaluated 78 male patients diagnosed with DSM-IVschizophrenia and 36 male control matched for age and IQ. All the patients under-went psychological testing and structural MRI. There were no significant correlatesbetween the level of insight and the whole brain, white and grey matter volumes.However, Laroi et al. [113] in a study looking at the relation between insightand frontal function in 21 medicated patients with schizophrenia and 21 controlsreported a possible association between poor insight and frontal lobe deficit, but noanatomical correlation with good insight. Out of the 21 patients with schizophrenia5 had slight and 2 moderate frontal atrophy, while the other did not show any signsof frontal lobe atrophy [113]. The divergences between the two studies could beunderstood as differences in patient selection, tools used and differences in numberof patients evaluated.

Clinical Considerations and Diagnosis

Cognitive Impairment and Cognitive Domains: Starting with Kraepelin and Bleuler,schizophrenia has been traditionally differentiated from affective psychoses. Thiscategorically informed perspective was later reinforced with a combination ofSchneiderian first ranks symptoms and a lack of concomitant affective symptomsthat were thought to be specific of schizophrenia. Standing on such giants’s shoul-ders it was easy to not see that cognitive deficits, more studied in schizophrenia,might not in fact be a schizophrenia-only type of problem. While there is evi-dence supporting the current psychiatric classification systems (i.e. DSM IVTR andICD-10) decision to maintain a categorical approach for schizophrenia versus affec-tive psychoses converging lines of evidence suggests that cognitive deficits, ratherthan being pathognomic of schizophrenia, and a “point of rarity” between differentdiagnoses, are a shared deficit between schizophrenia and affective psychoses [54,114, 115]. Furthermore it appears that within schizophrenia itself cognitive deficitsare present on a continuum rather as a constant, fixed factor [115].

Following an increase in the research community interest in cognition inschizophrenia The National Institute of Mental Health initiated the MATIRCSproject. By evaluating available factor analytic studies MATRICS aimed to define a

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consensus battery to examine cognitive outcomes in treatment studies of schizophre-nia [11]. A goal of this process was to identify the most relevant cognitive domainsof impairment in schizophrenia and identify the best existing tests to evaluatethese domains. Examining previous studies of the psychometric characteristics ofindividual tests and the factor structure of cognitive performance in schizophre-nia, 6 functional domains were selected and several candidate tests identified.The functional domains identified by MATRICS were Verbal Memory, VisualMemory, Processing Speed, Working Memory, Attention-Vigilance, and Reasoningand Problem Solving. Also MATRICS included a test of social cognition, but manystudies have found that social cognition may not be as strongly related to othercognitive measures, which are often referred to as “neurocognitive” tests.

These cognitive domains do reflect the current thinking about which aspects ofneuropsychological functioning are impaired in people with schizophrenia. It ismore controversial as to whether cognitive impairments in people with schizophre-nia reflect a distributed set of focal impairments as would be seen with regionallyspecific lesions, such as temporal or frontal lobe impairments, or whether theyare elements of a broad impairment that affects nearly all measurable cognitivedomains. We will first describe the domains and then evaluate the possibilitythat there are regionally-specific, focal impairments in schizophrenia or globaldeficits.

Processing Speed and Psychomotor Slowing: Processing speed refers to perfor-mance on tasks which require sustained high level effort and rapid responses. This islikely related to the concept of psychomotor slowing, but there are multiple possiblecontributors to impairments in processing speed. The most common test for assess-ing processing speed are the Symbol Digit Substitution Test and the TrailmakingTest, but often verbal fluency tests such as Animal Naming are considered to beprocessing speed tests as well. Meta analyses suggest that processing speed deficitsmay be the largest impairments in people with schizophrenia [116]. There are sev-eral on-going discussions regarding processing speed, including about the extent towhich the speed of processing reflects a common function with both mental andmotor aspects or two different processes: a cognitive deficit i.e. decreased speedof processing information and a motor deficit, specifically slowness in initiationand execution of a movement (psychomotor slowing) and whether processing speedactually underlies other impairments on the part of people with schizophrenia [117].

Attention and Vigilance: Impairments in both sustained and selective attention arewell known to be present in schizophrenia. Sustained attention is commonly referredto as “vigilance”, although it has been known for 30 years that the impairmentsare actually deficits in the ability to discriminate target and non-target informationand not in declining performance over time. Attention deficits e also promisingmarkers of vulnerability to the illness and are stable over time across changes inclinical state in people with the illness. The most common tests to measure vigi-lance are continuous performance tests (CPT) and these tests are used in severalversions, including tests that require detection of predetermined target sequences(e.g., 3–7) or detection of the same target occurring twice in sequence (e.g., IdenticalPairs “IP”).

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Verbal Learning and Memory: Impairments in verbal memory are among themost significant seen in schizophrenia, with deficits occurring in the ability to learn-ing information presented either once, such as a story learning tests, or multipletimes such as in list learning tests. There are several features of impairments seen inthese tests, which include lower performance on the first learning trial of list learningtests, reduced learning curves, and failure to spontaneously employ semantic strate-gies to aid recall. Interestingly, recognition memory performance does not appearto be notably impaired and prompts and cues (such as reminding the individual ofthe semantic categories) aids recall. These findings suggest that the impairments arenot like an amnestic condition such as Alzheimer’s disease where rapid forgettingis common and performance at delayed recall is almost entirely determined by theamount of information acquired during the learning trials. Verbal memory can bemeasured with list learning, story learning, and other similar tasks.

Visual Memory: Visual memory impairments in schizophrenia appear to be quitesimilar in their characteristics compared to verbal memory deficits. This area ofimpairment has been studied considerably less than verbal memory functioning.However, the MATRICS validation study, the level of impairment seen in visualmemory was similar to that seen in verbal learning and memory. Visual memorytests also have single presentation and multitrial learning formats.

Working Memory: Working memory has been a long-time target for study inschizophrenia, at least partially because of the findings of regional specificity ofcertain types of working memory. Working memory refers to the abilities requiredto maintain information on line and perform manipulations of the information.Working memory can include both spatial and verbal working memory and thereare suggestions that slightly different neural networks are involved in spatial, ver-bal, and object working memory. As working memory functions in primates showevidence of localization to the frontal lobes, some have referred to working memoryas an executive function. While there are clearly similarities to executive functionsin some of the cognitive tests used to measure working memory, these cognitiveprocesses have a number of distinctions. Typical tasks used to measure workingmemory include various forms of span tests (digit and spatial), n-back tests, andsequencing tests.

Reasoning and Problem Solving: There is a long history of description and studyof impairments in reasoning and problem solving in people with schizophrenia.Originating with classic descriptions of the “loss of abstraction” seen in schizophre-nia, this domain has been the center of a considerable amount of research. Several ofthe classic tests used in schizophrenia research, such as the Wisconsin Card sortingtest (WCST) examine reasoning and problem solving. Further, these tests have beencentral to the conception of impaired functioning in the frontal lobes, based on theresults of studies that used the WCST as a tool in neuroimaging studies. There aremultiple impairments seen in this domain, including deficits in performance on testsof abstraction such as proverbs, problem solving tests such as the WCST, and mazelearning tests.

Are these cognitive domains truly separable? Although the MATRICS initiativecharacterized the cognitive domains presented above as separable, there is no claim

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that they are independent. In fact, the results of several recent factor analytic studieshave suggested that the cognitive impairments may best be characterized by a singledimension. For example, in the large-scale CATIE study where over 1,300 patientsreceived a cognitive assessment, the best fitting factor model was unidimensional[118]. Other studies have also found that the best way to discriminate healthy indi-viduals and people with schizophrenia is by conceptualizing cognitive impairmentas a single dimension [119].

As noted above, processing speed is the single greatest deficit in people withschizophrenia. When abbreviated assessments are developed empirically, process-ing speed indices routinely are the single largest correlate of overall neuropsy-chological performance, as well as other important outcomes such as real-worldresidential functioning or performance-based indices of functional capacity. In theCATIE baseline study, four tests: digit symbol, verbal learning, grooved pegboard,and letter-number sequencing, accounted for 87% of the variance in the compos-ite score based on 22 different tests. These tests required an average of 19 minto complete, suggesting that quite robust estimates of overall performance on NPtests can be obtained with abbreviated assessments. This finding is consistent withthe results of studies aimed at developing abbreviated assessment batteries, whichhave routinely found that abbreviated assessments, either derived from longer bat-teries or developed de novo, are highly correlated with scores on longer assessments[120, 121].

In summary, there are multiple domains of cognitive impairment in schizophre-nia, but whether define a profile of impairment or a generalized pattern of impair-ment is not fully clear. Also, it is clear that global indices of performance arepredictable with quite abbreviated batteries and this may mean that there are fewertruly critical domains than has been believed in the past.

Negative Syndrome: The negative symptoms, specifically affective flattening,alogia, and avolition, is one of the five schizophrenia symptoms clusters (crite-rion A) in DSM IV-TR [8]. Asociability overlaps conceptually with DSM IV-TRcriterion B of social/occupational dysfunction. Other negative symptoms (e.g. anhe-donia) are discussed in the “Associated Features” section of the DSM chapter onschizophrenia.

The lack of affective reactivity is a typical example of a negative symptom. Undernormal circumstances most people have “full” affect, appropriately displaying arange of context dependent emotions. Patients with schizophrenia may present witheither decreased affective reactivity, in clinical parlor “reduced” or “limited range”of affect, or in extreme cases no affective reactivity, described clinically as bluntedor flat affect. Of note, the “negative symptom” label for affect refers to the range ofaffect and not to its content. In other words, affective content such as anger, disap-pointment etc., even if “negative” from a subjective perspective, cannot be labeledas a negative symptom.

Alogia (Greek α- a- “without” + λoγ oς logos “speech”) refers to decreasedverbal output. With the exception of neurological deficits that would impede thetranslation of thought in language, it is assumed that language is a fair repre-sentation of thought processes. Thus, alogia has been historically used to label

2 Neurocognitive Deficits, Negative Symptoms, and Insight in Schizophrenia 53

interchangeable (to some extent) manifestations, i.e. “poverty of (content of)speech” and “poverty of thought”, a global reduction in the quantity of thought.As such alogia was considered as a hallmark of the “negative formal thought dis-order” characteristic of schizophrenia. However, following DSM III emphasis onreliability and precise definitions, the preferred use for alogia is as a label for alanguage deficit [122]. One can further differentiate between “poverty of speech”,where the patient tends to answer briefly, with monosyllabic answers that frequentlyprompt further questioning for clarification purposes, and “poverty of content ofspeech”, where the patient’s answers, while long enough, are too vague, repetitive,over-abstract or over-concrete to be informative [122]. Clinically, alogia needs tobe differentiated from other manifestation of schizophrenia, including distractibility(either due to poor attention or attending to internal stimuli), thought blocking, anx-iety or a paranoid state. While it can also be a sign of depression (where alogia canbe secondary to severe apathy and anhedonia), severe mental retardation or demen-tia, a combination of primary alogia and other negative symptoms is most timescharacteristic of schizophrenia. Other explanations for decreased speech (secondaryalogia) include social anxiety, certain personality disorders, secondary gain, statesof acute intoxication, or, at times, the examiner’s inability to build rapport with thepatient.

Avolition (a “without” + volition/will) refers to the patient’s inability to initi-ate and maintain a goal directed activity or, in a more general sense, pursue anymeaningful, life enriching activities. The term is in fact imprecise as it is difficultto clinically differentiate avolition from amotivation, apathy and anhedonia. From aphenomenological standpoint these dysfunctions are more similar than different,even though theoretically they represent deficits of different neuropsychologicalfunctions.

Negative symptoms occur on continuum with normality, i.e. they are not qualita-tively but quantitatively different from normal states. They may also be secondaryto positive symptoms (e.g. patient gives up making day to day plans due to hisoppressive auditory hallucinations), depressive symptoms (depressed mood withanhedonia), chronicity, or medication adverse effects (e.g. anticholinergic effectsof low potency FGAs or anticholinergic add ons to prevent/treat EPS interpreted asanergia; EPS interpreted as flat affect). Furthermore, positive symptoms may mimicnegative symptoms (e.g. guarded, paranoid affect interpreted as flat; social isolationsecondary to paranoid delusions interpreted as asociality) [8, 14].

Thus, a careful clinical differential is necessary to diagnose primary negativesymptoms. The course of symptoms (persistent), a chronological, and a cause andeffect relationship can help illuminate the diagnosis. When in doubt, a case ofN = 1 experiment, where the patient’s symptoms are measured during an on/offdouble blind sequential intervention of interest trial should be considered.

Insight: For research and clinical purposes, insight could be defined along fivedimensions. These are: one’s awareness of mental disorder and social consequencesof illness, awareness of the need for treatment, awareness of symptoms in particu-lar and relatedness of symptoms to the disorder [123]. However, reflective capacityin one domain does not predict reflective capacity in other domains [124]. Overall,

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patients have more insight in the negative than the positive symptoms of the ill-ness [125]. Insight in the neurocognitive deficits has been shown to be extremelylimited even for patients who otherwise have a fair degree of insight [126, 127].Vos et al. [128] found a decrease in predictive ability in patients with schizophreniawhen compared with control. Decreased emotional awareness [129] and autonoeticawareness [130] has been reported patients with schizophrenia. Poor insight canalso result in decreased awareness of side effects of medications, such as tardivedyskinesia [131].

Course

Short term: Likely Secondary: Differentiating between phenomenologicaly similarprimary and secondary symptoms is essential in order to understand their shortversus long term course [20]. While primary symptoms are persistent, secondarysymptoms will improve once their cause is addressed. For example, if a negativesymptom is secondary to depressive symptoms, a relief in the negative symptomwill follow an improvement in the depressive symptomatology. Similarly, medica-tion adverse effects might mimic negative symptoms or result in cognitive deficits.When this is the case, discontinuing or changing the offending agent to a bettertolerated alternative [e.g. a first generation antipsychotic (FGA) to a second genera-tion antipsychotic (SGA)] will result in a decrease or disappearance of the observedsecondary symptom. A cause and effect relationship can be established if the rein-troduction of the suspected agent is followed by a re-appearance of the suspectedsymptom.

The short term course of insight has been studied in a prospective 6 weeks studyof 29 patients acutely hospitalized with DSM-III schizophrenia [132]. Insight intothe past symptoms but not into the current illness improved considerably duringthe observed period. Of note, insight was inversely correlated with the presence ofnegative symptoms at the follow up evaluations [132].

Premorbid and First Episode (FE)

Cognitive Impairment: Individuals who are destined to develop schizophrenia showdetectable cognitive differences compared to their peers as early as age 7. Thesefindings have been replicated in large samples of studies of individuals who arebeing conscripted into the military service in Israel and in Sweden [133]. Thesechanges are smaller than the impairments seen at the time of the first episode,roughly 0.5 SD worse than normative expectations, with this finding being quiteconsistent across studies. However, such a level of mean performance is not outsidethe normal range and in fact, 35% of general population performs at this level oflower. As a result, cognitive impairments are not useful as potential predictors ofrisk for the development of schizophrenia.

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The domains of impairment appear to be relatively general during the premorbidperiod, but some research has focused in on what may be a specific profile of risk.In children who manifested increased risk for schizophrenia as a function of havinga parent with the illness, global attentional deficits across multiple measures wereassociated with increased risk for the development of a psychotic disorder [134].

Some individuals who develop schizophrenia manifest a prodromal period thatis detectable between the premorbid and first episode stages of the illness. Duringthis prodromal period, there are a number of behavioral changes that are detectable.Cognitive changes during this period have been somewhat difficult to detect. Forinstance, it has been reported that at the time of onset of the prodrome, certaincognitive abilities such as episodic memory have already deteriorated to a level con-sistent with that seen during an active phase of illness. In a recent study, based on alarge-scale follow-up of clinical high risk [118] individuals who were manifestingprodromal symptoms, the individuals in the CHR group with the lowest cognitiveperformance scores on an 8-test cognitive battery were most likely to convert to apsychosis diagnosis. Further, within the cognitive battery, low scores on measuresof processing speed and verbal memory were the best predictors. These data suggestthat cognitive changes occur very early in prodromal periods and the largest changesoccur in individuals most likely to develop a psychotic condition.

Cognitive impairments appear to be fully developed at the time of the firstepisode of illness in those individuals who develop schizophrenia. Comparisonswith more chronic patients reveal similar profiles and severities of impairment, sug-gesting that progression may not be common during the early course of illness. A10 year longitudinal study demonstrated the stability of baseline cognitive deficits inFE patients compared with a group of healthy controls [135]. A recently publishedcomprehensive metanalysis reports significant deficits in FE patients compared totheir prior premorbid levels but a stable, chronic course after as well as no significantdifferences when comparing deficits in FE and chronic schizophrenia patients [12].In another very recent and methodologically sophisticated study, high risk, first-episode, and healthy individuals were followed up over a 6-month follow-up. Afteradjustment for practice effects and regression to the mean, it was found that a higherthan expected proportion of first episode patients improved on their verbal memoryperformance and a higher proportion than expected worsened in processing speedand working memory. Further, the at-risk subjects who converted to psychosis werealso found to worsen in these same two variables [136]. Thus, the issue of whetherthere is deterioration in cognitive functioning is still an open question. It is quiteclear that during this same time period, the first 10 years of illness, there are pro-gressive changes in brain volume, often found to be associated with more psychoticexacerbations. It has been suggested that standard clinical neuropsychological testsare less sensitive to functional decline than experimental tests with greater cognitivedemands.

Negative Syndrome: Andreasen’s negative symptoms, Crow’s type II, andCarpenter’s deficit schizophrenia are all characterized by an insidious onset [9, 13,14, 19, 20, 23]. Negative symptoms are fairly prevalent in first episode patients withschizophrenia, with estimated rates of 35–70% during relatively short (less than

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2 years) longitudinal studies [80, 137, 138]. Studies of first-episode schizophreniapatients reported that flat affect is present at the onset of illness [34]. The age ofonset appears to play a role in the course of negative symptoms. In a population ofchronically institutionalized schizophrenia patients an earlier onset was associatedwith greater numbers of negative symptoms throughout life [139]. In a sample ofpatients who did not meet criteria for schizophrenia but were diagnosed as vulnera-ble to psychosis negative symptoms were significantly correlated with quality of life(QOL) and with global function as measured by the global assessment of function(GAF) scale [8, 140]. Premorbid social competence scores and premorbid schizoidtraits significantly predicted the presence of negative symptoms 10 years later isschizophrenia/schizoaffective sample [141].

Insight: Insight impairment is also common in early schizophrenia and has beenassociated with cognitive and executive declines in multiple domains [142, 143].During the prodrome of schizophrenia, the level of insight inversely correlateswith the need of acute services [144]. This finding is possibly associated withthe several factors: better support systems, treatment seeking behavior earlier inthe course of relapse, and better compliance with treatment recommendations [85,145]. For FE schizophrenia, lack of insight was a strong predictor of involuntaryhospitalization [146].

Long Term Course

Cognitive Impairment: Regardless of the course of cognition in schizophrenia inearly and mid life, there is quite consistent evidence that a least some people withschizophrenia show deterioration in their functioning in their later years. Patientswith a history of long-term institutional stay and extremely severe and refractorypositive symptoms have been shown to have subtle worsening in their cogni-tive functioning over a variety of follow-up periods [147]. While the presence ofdegenerative conditions such as Alzheimer’s disease or vascular dementia does notexplain these changes, some recent evidence suggests that normal-range presence ofaging related changes may actually relate to risk for cognitive decline. We recentlyreported on a postmortem study of 110 patients with schizophrenia and found thatthe number of hippocampal neurofibribrillary tangles and cortical neurotic plaqueswere correlated with the severity of cognitive impairments [148]. Further ApoE4carrier status was also associated with severity of cognitive impairment and theinteraction of carrier status and the interaction of carrier status and plaque countwas also a significant contributor.

Finally, we have also recently shown that the current presence of institutional-ization is not driver of cognitive changes in older people with schizophrenia [149].Examining a large sample of community dwelling older people with schizophreniawho varied widely in the longest institutional stay (from 1 week to 30 years), wefound a correlation between longest hospitalization and risk for decline in scoreson a performance-based measure of everyday living skills. We found that all of the

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older people with schizophrenia, across institutional stay, showed evidence of cog-nitive worsening when compared to healthy controls, who manifested a practiceeffect. As previously reported, older patients with schizophrenia failed to mani-fest normal practice effects on neuropsychological tests, which is itself evidenceof impaired performance. In the Granholm et al. [150] study, the older the patientswith schizophrenia, the smaller their practice effects were after reassessment.

Negative Syndrome: The different types of schizophrenia with predominant neg-ative symptoms, starting with Kraepelin Dementia Praecox and including modernday typologies, i.e. Andreasen’s negative symptoms type, Crow Type II, as wellas the deficit syndrome of schizophrenia, share a chronic course [1, 9, 13, 14,18–20, 23]. While a poor response to D2 antagonists, the cornerstone of schizophre-nia therapy at the time of Crow’s and Andreasen’s modern classifications, mighthave added to the impression of a chronic course, long term prospective studies havesince confirmed this symptoms cluster persistence and stability over time. Negativesymptoms appear to be not only persistent but also increasing with age [36]. In across sectional study of 272 patients with schizophrenia divided in 4 age groupsaging was associated with increased symptom severity [37]. In a retrospective studyof 99 chronically institutionalized patients the lifelong course of schizophrenia wascharacterized by a decrease in positive symptoms and an increase in negative symp-toms [139]. Prospective studies also confirmed Kraepelin’ observation about thechronic course of deficit symptoms. The longitudinal Munich study, one of thelonger and the largest prospective study of schizophrenia to date, found that first-hospitalized patients had significantly more negative symptoms 15 years later [81,82]. Putnam et al., in a prospective 1 year-long study of geriatric inpatients withschizophrenia, reported a significant increase in negative symptom severity over thestudy period [151]. Of note, both Putnam et al. [151] and Mancevski et al. [139] con-clusions are limited by an implicit selection bias. Putnam et al. [151] only includedinpatient geriatric schizophrenia patients, while Mancevski et al. [139] includedrecords for patients who remained in state hospitals as inpatiens through the deinsti-tutionalization of the 1950s and 1960s and eventually died in a psychiatric hospital.A prospective 1 year long outpatient study comparing 63 patients with flat affectwith 99 patients without (non flat affect) reported that flat affect was correlated withpoorer premorbid adjustment, worse current quality of life, and worse outcome at1-year follow-up [34].

Insight: In a cross sectional study of 111 patients diagnosed with schizophre-nia using DSM-III criteria Cernovsky et al. [152] reported that 97.3% showed poorinsight at same point during their illness and 58.6% at the time of assessment. Inthis study, patients with poor insight were more likely to display poor judgment, lessreliable reports, were more preoccupied with delusions, less educated and sociallywithdrawn. While the level of insight was not correlated with outcome, the presenceof insight at the first assessment predicted less need of psychiatric hospitalizationand better compliance with treatment, independent of environment. In another study,schizophrenia patients with involuntary admissions showed diminished awarenessof illness when compared with voluntary admitted schizophrenia patients [153].Furthermore, poor insight was correlated with higher need of hospitalization at

58 A. Preda et al.

2 1/2 and 3 1/2 follow up. The level of insight into the presence of illness and needfor treatment increased significantly only in patients with voluntary hospitalization,compared with the ones with involuntary hospitalizations for the follow up period.Poor insight also correlates with negative symptoms, delusion of grandeur and sex-ual delusions, thought broadcasting and poor premorbid adjustment at onset ofillness [154]. Medalia and Thysen [126, 127] report that patients with schizophreniahad significantly less insight into their neuro-cognitive symptoms than their clinicalsymptoms.

Treatment Considerations

Biological Interventions

Antipsychotics

First Generation Antipsychotics (FGAs): Traditional antipsychotic medications haveno efficacy in the treatment of primary negative symptoms or cognitive impairment,beyond occasional improvement in attention [155–157].

Droulout et al. [158] found a strong correlation between low level of insight andpoor medication adherence. Furthermore, insight was correlated with medicationadherence independently of patients demographic and other clinical characteris-tics. In another study, low insight at the onset of schizophrenia predicted poormedication adherence at 6 months follow up [159]. Subjective response to antipsy-chotic medication was correlated with insight and paranoid ideation [160]. Sajatovicet al. [161] report that in a sample of 47 patients with schizophrenia (N = 33) andschizoaffective disorder (N = 12) treated with first and second generation antipsy-chotic medications or mixed treatment, only the patients treated with first generationantipsychotics showed significant improvement in their attitude toward medications.However, the change was not large enough to differentiate between groups.

Second Generation Antipsychotics (SGAs)

Cognitive Impairment: The evidence supporting the cognitive benefits or superiorityfor negative symptoms of SGAs versus FGAs is mixed. Two large, publicly funded,pragmatic trials comparing SGAs versus FGAs, CATIE [162] and CUtLASS [163]did not support prior claims of SGAs superiority in terms of global effectiveness,quality of life or specific domain improvement [163, 164]. CATIE did report a mod-est improvement over a 12 months period in a combined measure for psychosocialfunctioning (Quality of Life Scale) that includes a number of negative symptoms[165]. However, there were no significant differences between the different SGAagents and perphenazine. The interpretation of these results is further limited bythe fact that negative symptoms change was not directly assessed. Also, due toa high dropout rate the QLS outcome could be assessed only in one-third of thepatients who started the trial, which further limits the interpretation of the study

2 Neurocognitive Deficits, Negative Symptoms, and Insight in Schizophrenia 59

results. Furthermore in their meta-analysis of 150 RCTs including 21,533 patientscomparing 9 SGAs with FGAs, Leucht et al. [162] did not find that SGAs weremore efficacious for negative symptoms or quality of life (as a proxy for cognitiveeffects; of note, overall cognition or specific cognitive domains were not specificallyassessed). However, in a meta-analysis focused on cognitive outcomes, including 18RCTs with 1,837 patients, Guilera et al. [166] found that SGAs produced a slightimprovement in the global cognitive index and in several cognitive domains (3 out11 domains tested), compared with typical antipsychotics [166]. Due to a smalleffect size and as the potential for publication bias could not be excluded, due to arestricted search, Guilera et al. [166] conclusions should be treated with caution.

Negative Syndrome: In a randomized, placebo controlled study of 61 patientswith refractory schizophrenia and partial response to clozapine, adding aripiprazole5–30 mg to clozapine reduced negative symptoms over an 8 weeks period [167].

Insight: In a 52 weeks double-blind trial of 323 patients with schizophreniaor schizoaffective disorder receiving risperidone long-acting injectable, Gharabawiet al. [168] reported that insight scores correlated significantly with CGI-S,PANSS subscales, Strauss-Carpenter Levels of Functioning, and Personal andSocial Performance (PSP). Overall, insight scores improved significantly at end-point observation period [169]. Aguglia et al. [170] reported improvement in insightin patients diagnosed with schizophrenia who were switched from conventional toatypical antipsychotic medication. However, in another study, only patients on firstgeneration antipsychotics had significant improvement in the insight domain andwas no differences between the groups of patients treated with first, second andmixed first and second generation antipsychotics in terms of insight [161]. Thisobservation of no differences in insight in patients treated with first or second gen-eration antipsychotics, was also supported by Buckley et al. [171] Less awarenessinto the symptoms predicted a poor drug attitude, however, there were no differencesin attitude between first and second generation antipsychotics.

Antidepressants: In a metaanalysis of 11 studies (393 patients with schizophre-nia spectrum disorders) selective serotonin re-uptake inhibitor augmentation did notimprove the negative symptoms of schizophrenia [172].

Other Medications: Even though theoretically justified based on the underlyingetiophysiology no gabaergic, glutaminergic, acethylcholinergic or other compoundshave been established as efficacious for the treatment of negative symptoms orcognitive deficits in schizophrenia. Multiple studies have been conducted with-out notable success. As we noted elsewhere [173], methodological issues are notresponsible for these failures.

Other Biological Interventions

Negative Syndrome: A meta-analysis of 9 trials (N = 213 patients) found a smallto moderate effect size for repetitive transcranial magnetic stimulation (rTMS) fornegative symptoms in schizophrenia. The effect size increased with changes in therTMS dose and duration, with larger effect size found for stimulation above 10 Hzand duration of treatment longer than 3 weeks [174].

60 A. Preda et al.

Psychological Interventions

Negative Syndrome and Insight Deficits: The number of CBT trials for nega-tive symptoms and insight in schizophrenia is relatively small; however based onthe available results CBT appear as a promising intervention for these clinicaldomains of schizophrenia. Nieznanski et al. [175] reported improved insight scoresin patients who received 12 sessions of cognitive skills training versus psychoeduca-tion. In a large (N = 422) multisite randomized controlled trial comparing nurse-ledcognitive behavior therapy (6 sessions over 2–3 months) with treatment as usual,CBT improved insight, reduced negative symptoms and increased time to relapseand reduced number of inpatient days [176]. The gains were shown at 1 year inthe CBT group. No improvement was found for overall symptoms, and positivesymptoms, which is consistent with the view that insight and negative symptomsare independent clinical domains. Of note, at 1 year the groups did not separate interms of return to work/ school, which suggest that the insight/negative symptomseffect might need more than 1 year to result in functional outcome improvement.Cognitive deficits were not assessed in this study.

In a review, Lewis [177] suggested that suicidal risk in schizophrenia can bereduced by working through the grief associated with facing the developing ill-ness and attaining an usable insight that integrate both affective and cognitivecomponents.

Cognitive Remediation in Schizophrenia

Behavioral cognitive remediation has been shown recently to produce cognitivechanges and lead to relevant real-world functional improvements. Several of theseapproaches have shown positive effects that are durable even months after the behav-ioral intervention is terminated (e.g., McGurk et al. [178]). While previous resultswere often less positive, there have been several independent findings of cogni-tive enhancement leading to functional improvements. For instance, Vinogradovet al. [179] found that cognitive enhancement therapy lead to an improvement inlevels of BDNF, a change not detected in a sample of people with schizophreniawho were exposed to video games during the same time period. Further, usingstrategies that focus on executive functioning and multiple components of cog-nitive abilities at the same time have led to the largest successes. McGurk andcolleagues found that cognitive training (involving computerized training and plan-ning skills) in combination with a supportive employment program yielded notjust improved cognition, but higher retention rates in the program, fewer depres-sive symptoms, more time working, and higher wages than those in supportedemployment alone. Similarly, the work of Wexler and Bell [180] supports theuse of cognitive remediation as a method for improving outcomes work out-comes, with a 2-year follow-up of their patients showing similar positive long-termoutcomes [181].

2 Neurocognitive Deficits, Negative Symptoms, and Insight in Schizophrenia 61

Functional Relevance of Cognition, Negative Symptoms andInsight in Schizophrenia

A discussion about function needs to first define function and then clarify, withinthe parameters of the specific function definition, what constitutes ideal functioningwhich is no easy task considering there is no consensus on what might representideal functioning. It is understood that “good function” is relative and depends bothon the subject’s own agenda as well social and cultural, time and place specificfactors. A systematic way of accounting for these variables can be organized along 3main dimensions: (1) subjective wellbeing/satisfaction (2) functioning in daily life,and [114] external resources and social support. This is the basis of the Quality ofLife (QOL) concept, a complex construct that is generally agreed as a good enoughfunctional outcome [182].

Cognitive Impairment: One of the major reasons for the increased interest incognition in schizophrenia is functional relevance. Cognitive impairments are strongpredictors of the impairments in real-world functioning that affect many people withschizophrenia [183]. Previous speculation was aimed at whether there were specificrelationships between domains of cognitive functioning and specific real-world out-comes such as social and vocational milestones. At this time, the research findingsare inconsistent in terms of specific relationships between cognitive functions andaspects of functional outcomes. As noted above, processing speed is a major con-tributor to the prediction of real-world outcomes much like it contributes to theprediction of overall cognitive performance.

One recent development in the study of cognition and functioning in schizophre-nia is that of performance-based assessment of everyday functional skills, oftenreferred to as assessment of “functional capacity” [184]. These assessmentinstruments are similar to neuropsychological tests in that they are designedto measure performance, not self-report, and to have suitable psychometriccharacteristics in domains of test retest reliability, sensitivity to change withtreatments. These measure tap a number of aspects of functioning, includ-ing social, vocational, and residential skills. Further, the latest stages of theMATRICS process also include these indices as co-primary measures of treatmentoutcomes.

Several studies have suggested that the “true” causal influence between cog-nitive impairments and real-world functional deficits is through the impact ofcognitive deficits on functional capacity. These studies have shown that cog-nitive performance measures add relatively little incremental prediction of realworld functioning after functional capacity measures are considered [185]. In addi-tion, these measures have shown excellent validity across different psychiatricdiagnoses and appear to predict real-world outcomes quite similarly in bipolarand schizophrenia patients and in schizophrenia patients across different WesternCultures.

Negative Syndrome: The deficit or negative syndrome of schizophrenia has gen-erally been considered too have a poor a poor prognosis due to its chronic course,and generally poor response to medications [9, 14, 18].

62 A. Preda et al.

The predictive value of negative symptoms has been analyzed in a prospective10-year follow up study of patients with schizophrenia/schizoaffective disorder,non-psychotic disorders and other psychotic disorders [141]. Negative symptomswere predictive of work functioning and cognitive deficits at later follow-up forthe full study sample; in addition, a divided by group analysis showed significantresults for the schizophrenia/schizoaffective group only, which might indicate moresecondary negative symptoms in the other groups [141].

Converging line of evidence including cross sectional studies, retrospective andprospective studies consistently show that negative symptoms have been associ-ated with a poor overall outcome. In a prospective 1-year study comparing 63flat affect patients and 99 non flat affect patients flat affect correlated with worsequality of life (cross sectional measure) and worse outcome at the final 1 yearfollow up [34]. A longitudinal FE study with a 7-year follow-up reported thatnegative symptoms at intake, in addition to verbal memory, processing speed andattention, predicted global psychosocial functioning [186]. In a prospective 10-yearstudy negative symptoms correlated with concurrent and prospective impairmentsin social functioning at all three study visits (i.e. 4.5-, 7.5- and 10-year follow-ups) with deficits in work functioning and higher rehospitalization rates at twoof the three follow-up visits [141]. Finally, the prospective large sample Munichstudy of first hospitalized patients found that a negative syndrome at dischargeindicated a poor outcome (as measured by Global Assessment Scale) 15 yearslater [81, 187].

Insight: It has been estimated that between 30 and 50% of patients withschizophrenia have poor insight (for a review, see Baier [188]). Hwang et al.suggests that better insight is predicted by the presence of affective symptomssuch as depression and anxiety [189]. Sevy et al. [190] proposed that lackof insight into the symptoms correlates with severity of illness in schizophre-nia. However, patients with schizophrenia with better insight can have moreaffective symptoms and suicidal ideation, which in turn could affect quality oflife [191].

Interestingly, when it comes to insight an early onset of schizophrenia appearsto carry a better prognosis: Heinrichs et al. [86] found that in 63% of the earlyschizophrenia patients have preserved insight, which in turn correlated with sig-nificantly lower hospitalization rate when compared to patients with poor insight.Early improvement of insight in FE schizophrenia appear to also predict a betteroutcome at 1 year follow up [192]. According to the report from family members ofpatients with schizophrenia, as the illness progresses, the number of patients withgood insight can decrease to 27% [193]. Yen et al. [194] in a study of 74 Chineseoutpatients with schizophrenia in remission reported that from all the insight dimen-sions only insight into treatment was associated with less hospitalization and bettersocial adjustment. Llorca [195] reports that a lack of insight correlates with poor orpartial compliance and that in turn, is associated with poor outcome. Overall, insightpredicts relapse and remission in patients with schizophrenia [196].

2 Neurocognitive Deficits, Negative Symptoms, and Insight in Schizophrenia 63

Cross Relationships

The relationship between cognitive and negative symptom: Both the primary neg-ative symptoms and cognitive dysfunction domains appear to share a number ofcharacteristics: 1. They are relatively independent of the psychotic, affective andsecondary negative symptoms domains, which tend to vary together in correlationwith the course of illness and response to medications; 2. They have long term sta-bility; 3. They respond poorly to available antipsychotic treatments; 4. They areboth correlated with prognosis; 5. They are correlated with outcome, specificallywith social and functional outcomes.

The relationship between cognitive deficits and insight: Sevy et al. [190]suggested that poor insight into consequence of illness correlates with positivesymptoms and poor insight into the need for treatment correlates with poor cog-nition. Lack of awareness in various aspects of the illness specifically correlateswith degree of impairment in cognitive, affective and psychotic symptoms [197].Interestingly, patients with a fair degree of overall insight can show severe insightdeficits into their cognitive impairments [198].

The relationship between insight and negative symptoms: A number of studiesshowed that lack of insight correlates with prognosis and functional/social out-comes; similarly, prognosis and social isolation correlate with negative symptoms[199]. While these correlations suggest that these might be somewhat interconnecteddomains, the nature and strength of the insight – negative symptoms relationshipis far from clear. In their metanalysis of 20 studies (N = 1,487 subjects) Mintzet al. [123] reported a significant inverse correlation with a mean effect size of–0.23 (CI = –0.48–0.02), indicating that as negative symptoms increased, over-all insight decreased. Four out of the five tested insight dimensions were inverselycorrelated and significant: awareness of mental disorder –0.20; attribution of symp-toms to disorder –0.33; understanding of the social consequences of disorder –0.40;and awareness of the need for treatment –0.40). The relatively modest effect sizesfor awareness of mental disorder (–0.20) and attribution of symptoms to disor-der (–0.33) are harder to interpret. The moderate effect sizes for awareness of thesocial consequences of disorder (–0.40) and need for treatment (–0.40) might be yetanother indication of the fact that negative symptoms correlate with social dysfunc-tion. Mintz et al. [123] also reported an older age of onset effect on the relationshipbetween negative symptoms and insight: the older the patient was at the onset ofillness the stronger the negative correlation. Of note, this finding is at odds withpreexistent literature suggesting that the younger the patient the higher the risk ofnegative and cognitive symptoms [35]. The modest to moderate at best effect sizesof this study have been interpreted as an indication that insight might represent aseparate symptom domain [41]. Further supporting this hypothesis, in a prospective6-months, multi-site, open-label, risperidone long-acting injection phase IV trial of303 subjects with recent onset (≤2 years) schizophrenia injection Wiffen et al. [41]reported that changes in insight did not correlate with changes in total symptoms

64 A. Preda et al.

or negative symptoms which further suggests that this might possibly be indepen-dent symptom domains. More studies are needed for a conclusive resolution of thesequestions.

Discussion

In this review we presented in parallel characteristic aspect of 3 symptoms domainsof schizophrenia that have been traditionally linked to one another: neurocognitivedeficits, negative symptoms and insight deficits. Differentiating between primaryand secondary symptoms (for all the discussed domains) is paramount. Primarysymptoms show a number of common characteristics across domains: a correlationwith premorbid level of functioning, a chronic course, and a relative independenceof other symptom domains (i.e. positive symptoms). Insight appears to inverselycorrelate with low mood and anxiety, which is not the case for the other domains.However, this finding might also be an artifact of a poor separation between pri-mary and secondary insight deficits. In terms of neurobiological correlates there isa partial overlap between cognitive and negative symptoms; however specific neu-robiological correlates have also been reported. The neurobiology of insight is evenless clear.

While all three domains are associated with poor prognosis and poor functionaloutcomes, negative symptoms and cognitive deficits share a positive association(i.e. higher severity results in poorer prognosis and outcomes), while insightcorrelates negatively (i.e. better insight correlates with poorer prognosis and out-come. Furthermore, negative symptoms and cognitive deficits appear to have anindependent effect on prognosis and outcome.

Available interventions are generally ineffective for negative symptoms andcognitive deficits and have shown mixed results for insight.

We conclude that despite apparent similarities and partial overlaps insightdeficits, negative symptoms and cognitive deficits are separate symptom domainsof schizophrenia. There is a stronger relationship between cognitive deficits andnegative symptoms than between insight and negative symptoms or cognitivedeficits.

This conclusion has important applications. At a theoretical level the implicationis that, similarly to its clinical presentation, the underlying neurocircuitry and patho-physiology of schizophrenia is diffuse and heterogeneous rather than localized andhomogeneous. At a more pragmatic level the relative independence of the insight,cognitive and negative symptoms suggests that effective interventions might need toselectively target each of the domains.

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